Methods for selecting headache patients responsive to botulinum toxin therapy

ABSTRACT

A method for treating a headache by selecting a patient determined to be responsive to administration of a botulinum neurotoxin for treatment of a headache by determining that the patient has or has a propensity to have an imploding headache and/or an ocular headache pain and administering a botulinum toxin to the patient, thereby treating the headache. A method for selecting from a population of patients with headache or with a propensity to have a headache, those patients whose headache will respond to administration of a botulinum neurotoxin by identifying from a population of patients with headache or with a propensity to have a headache those patients who have or who have a propensity to have an imploding headache pain and/or an ocular headache pain.

BACKGROUND

The present invention relates to methods for selecting a patientresponsive to a headache treatment and to methods for treating aheadache. In particular, the present invention relates to methods forselecting a patient responsive to treatment of a headache with abotulinum toxin and to methods for treating a headache with a botulinumtoxin.

A headache is a pain in the head, such as in the scalp, face, foreheador neck. A headache can be a primary headache or a secondary headache. Aprimary headache is a headache that is not caused by another condition.Contrarily, a secondary headache is due to a disease or medicalcondition, such as an illness, infection, injury, stroke or otherabnormality. Thus, with a secondary headache there is an underlyingdisorder that produces the headache as a symptom of that underlyingdisorder. Tension headache is the most common type of primary headacheand tension headaches account for about 90% of all headaches. A tensionheadache is often experienced in the forehead, in the back of the headand neck, or in both regions. It has been described as a tight feeling,as if the head were in a vise. Soreness in the shoulders or neck iscommon. Nausea is uncommon with a tension headache.

Migraine headaches are recurrent headaches that may be unilateral orbilateral. Migraine headaches may occur with or without a prodrome. Theaura of a migraine may consist of neurologic symptoms, such asdizziness, tinnitus, scotomas, photophobia, or visual scintillations(eg, bright zigzag lines). Migraines without aura are the most common,accounting for more than 80% of all migraines.

An estimated 10-20% of the population suffers from migraine headaches.An estimated 6% of men and 15-17% of women in the United States havemigraine. Migraines most commonly are found in women, with a 3:1female-to-male ratio.

About 2% of all headaches are secondary headaches. For example, acervicogenic headache is a headache which is due to a neck problem, suchas an abnormality of neck muscles, which can result from prolonged poorposture, arthritis, injuries of the upper spine, or from a cervicalspine disorder. Sinus headache is another type of secondary headache. Asinus headache can be caused by inflammation and/or infection in theparanasal sinuses.

An ocular headache (i.e. opthalmoplegic migraine) presents with alateralized pain (often around the eye) often accompanied by nausea,vomiting, and double vision. With ocular headache visual disturbancesare common and can include visual hallucinations, such as sparks, lightflashes, zigzags of light or visual field defects. The patient canreport pain or pressure on or in his eyes. An ocular headache pain is apain which is localized in or around the eye.

A headache (such as a migraine headache) can be accompanied by anexploding headache pain. An exploding headache pain has the seminaldiagnostic characteristic of perception by the patient of a pressure orforce being exerted within the skull (that is within the head) in anoutward fashion. The patient can report that it feels as if his head isgoing to explode, as if his head will split open, and/or that it feelsas if someone is stabbing him inside his head. Thus, in an explodingheadache the pain is perceived by the patient as a type of pain thatmoves from the inside to the outside of the head. Contrarily, a headache(such as a migraine headache) can be accompanied by an implodingheadache pain. An imploding headache pain has the seminal diagnosticcharacteristic of perception by the patient of a pressure or force beingexerted from outside of the skull in an inward fashion. The patient canreport that it feels as if something heavy is sitting on his head (suchas on his forehead), as if something is squeezing his head, as ifsomething is tightening a vice on his head, and/or as if a sharp objectis being inserted into his head. Thus, in an imploding headache the painis perceived by the patient as a type of pain that moves from theoutside to the inside of the head.

Botulinum Toxin

The genus Clostridium includes more than one hundred and twenty sevenspecies, grouped according to their morphology and functions. Theanaerobic, gram positive bacterium Clostridium botulinum produces apotent polypeptide neurotoxin, botulinum toxin, which causes aneuroparalytic illness in humans and animals referred to as botulism.The spores of Clostridium botulinum are found in soil and can grow inimproperly sterilized and sealed food containers of home basedcanneries, which are the cause of many of the cases of botulism. Theeffects of botulism typically appear 18 to 36 hours after eating thefoodstuffs infected with a Clostridium botulinum culture or spores. Thebotulinum toxin can apparently pass unattenuated through the lining ofthe gut and attack peripheral motor neurons. Symptoms of botulinum toxinintoxication can progress from difficulty walking, swallowing, andspeaking to paralysis of the respiratory muscles and death.

Botulinum toxin type A is the most lethal natural biological agent knownto man. About 50 picograms of a commercially available botulinum toxintype A (purified neurotoxin complex)¹ is a LD₅₀ in mice (i.e. 1 unit).One unit of BOTOX® contains about 50 picograms (about 56 attomoles) ofbotulinum toxin type A complex. Interestingly, on a molar basis,botulinum toxin type A is about 1.8 billion times more lethal thandiphtheria, about 600 million times more lethal than sodium cyanide,about 30 million times more lethal than cobra toxin and about 12 milliontimes more lethal than cholera. Singh, Critical Aspects of BacterialProtein Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited byB. R. Singh et al., Plenum Press, New York (1976) (where the stated LD₅₀of botulinum toxin type A of 0.3 ng equals 1 U is corrected for the factthat about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of botulinumtoxin is defined as the LD₅₀ upon intraperitoneal injection into femaleSwiss Webster mice weighing 18 to 20 grams each. ¹Available fromAllergan, Inc., of Irvine, Calif. under the tradename BOTOX® in 100 unitvials)

Seven generally immunologically distinct botulinum neurotoxins have beencharacterized, these being respectively botulinum neurotoxin serotypesA, B, C₁, D, E, F and G each of which is distinguished by neutralizationwith type-specific antibodies. The different serotypes of botulinumtoxin vary in the animal species that they affect and in the severityand duration of the paralysis they evoke. For example, it has beendetermined that botulinum toxin type A is 500 times more potent, asmeasured by the rate of paralysis produced in the rat, than is botulinumtoxin type B. Additionally, botulinum toxin type B has been determinedto be non-toxic in primates at a dose of 480 U/kg which is about 12times the primate LD₅₀ for botulinum toxin type A. Moyer E et al.,Botulinum Toxin Type B: Experimental and Clinical Experience, beingchapter 6, pages 71-85 of “Therapy With Botulinum Toxin”, edited byJankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxinapparently binds with high affinity to cholinergic motor neurons, istranslocated into the neuron and blocks the release of acetylcholine.Additional uptake can take place through low affinity receptors, as wellas by phagocytosis and pinocytosis.

Regardless of serotype, the molecular mechanism of toxin intoxicationappears to be similar and to involve at least three steps or stages. Inthe first step of the process, the toxin binds to the presynapticmembrane of the target neuron through a specific interaction between theheavy chain, H chain, and a cell surface receptor; the receptor isthought to be different for each type of botulinum toxin and for tetanustoxin. The carboxyl end segment of the H chain, H_(C), appears to beimportant for targeting of the toxin to the cell surface.

In the second step, the toxin crosses the plasma membrane of thepoisoned cell. The toxin is first engulfed by the cell throughreceptor-mediated endocytosis, and an endosome containing the toxin isformed. The toxin then escapes the endosome into the cytoplasm of thecell. This step is thought to be mediated by the amino end segment ofthe H chain, H_(N), which triggers a conformational change of the toxinin response to a pH of about 5.5 or lower. Endosomes are known topossess a proton pump which decreases intra-endosomal pH. Theconformational shift exposes hydrophobic residues in the toxin, whichpermits the toxin to embed itself in the endosomal membrane. The toxin(or at a minimum the light chain) then translocates through theendosomal membrane into the cytoplasm.

The last step of the mechanism of botulinum toxin activity appears toinvolve reduction of the disulfide bond joining the heavy chain, Hchain, and the light chain, L chain. The entire toxic activity ofbotulinum and tetanus toxins is contained in the L chain of theholotoxin; the L chain is a zinc (Zn++) endopeptidase which selectivelycleaves proteins essential for recognition and docking ofneurotransmitter-containing vesicles with the cytoplasmic surface of theplasma membrane, and fusion of the vesicles with the plasma membrane.Tetanus neurotoxin, botulinum toxin types B, D, F, and G causedegradation of synaptobrevin (also called vesicle-associated membraneprotein (VAMP)), a synaptosomal membrane protein. Most of the VAMPpresent at the cytoplasmic surface of the synaptic vesicle is removed asa result of any one of these cleavage events. Botulinum toxin serotype Aand E cleave SNAP-25. Botulinum toxin serotype C, was originally thoughtto cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Eachof the botulinum toxins specifically cleaves a different bond, exceptbotulinum toxin type B (and tetanus toxin) which cleave the same bond.Each of these cleavages block the process of vesicle-membrane docking,thereby preventing exocytosis of vesicle content.

Botulinum toxins have been used in clinical settings for the treatmentof neuromuscular disorders characterized by hyperactive skeletal muscles(i.e. motor disorders). In 1989 a botulinum toxin type A complex hasbeen approved by the U.S. Food and Drug Administration for the treatmentof blepharospasm, strabismus and hemifacial spasm. Subsequently, abotulinum toxin type A was also approved by the FDA for the treatment ofcervical dystonia and for the treatment of glabellar lines, and abotulinum toxin type B was approved for the treatment of cervicaldystonia. Non-type A botulinum toxin serotypes apparently have a lowerpotency and/or a shorter duration of activity as compared to botulinumtoxin type A. Clinical effects of peripheral intramuscular botulinumtoxin type A are usually seen within one week of injection. The typicalduration of symptomatic relief from a single intramuscular injection ofbotulinum toxin type A averages about three months, althoughsignificantly longer periods of therapeutic activity have been reported.

Although all the botulinum toxins serotypes apparently inhibit releaseof the neurotransmitter acetylcholine at the neuromuscular junction,they do so by affecting different neurosecretory proteins and/orcleaving these proteins at different sites. For example, botulinum typesA and E both cleave the 25 kiloDalton (kD) synaptosomal associatedprotein (SNAP-25), but they target different amino acid sequences withinthis protein. Botulinum toxin types B, D, F and G act onvesicle-associated protein (VAMP, also called synaptobrevin), with eachserotype cleaving the protein at a different site. Finally, botulinumtoxin type C₁ has been shown to cleave both syntaxin and SNAP-25. Thesedifferences in mechanism of action may affect the relative potencyand/or duration of action of the various botulinum toxin serotypes.Apparently, a substrate for a botulinum toxin can be found in a varietyof different cell types. See e.g. Biochem J 1; 339 (pt 1):159-65:1999,and Mov Disord, 10(3):376:1995 (pancreatic islet B cells contains atleast SNAP-25 and synaptobrevin).

The molecular weight of the botulinum toxin protein molecule, for allseven of the known botulinum toxin serotypes, is about 150 kD.Interestingly, the botulinum toxins are released by Clostridialbacterium as complexes comprising the 150 kD botulinum toxin proteinmolecule along with associated non-toxin proteins. Thus, the botulinumtoxin type A complex can be produced by Clostridial bacterium as 900 kD,500 kD and 300 kD forms. Botulinum toxin types B and C₁ is apparentlyproduced as only a 700 kD or 500 kD complex. Botulinum toxin type D isproduced as both 300 kD and 500 kD complexes. Finally, botulinum toxintypes E and F are produced as only approximately 300 kD complexes. Thecomplexes (i.e. molecular weight greater than about 150 kD) are believedto contain a non-toxin hemaglutinin protein and a non-toxin andnon-toxic nonhemaglutinin protein. These two non-toxin proteins (whichalong with the botulinum toxin molecule comprise the relevant neurotoxincomplex) may act to provide stability against denaturation to thebotulinum toxin molecule and protection against digestive acids whentoxin is ingested. Additionally, it is possible that the larger (greaterthan about 150 kD molecular weight) botulinum toxin complexes may resultin a slower rate of diffusion of the botulinum toxin away from a site ofintramuscular injection of a botulinum toxin complex.

In vitro studies have indicated that botulinum toxin inhibits potassiumcation induced release of both acetylcholine and norepinephrine fromprimary cell cultures of brainstem tissue. Additionally, it has beenreported that botulinum toxin inhibits the evoked release of bothglycine and glutamate in primary cultures of spinal cord neurons andthat in brain synaptosome preparations botulinum toxin inhibits therelease of each of the neurotransmitters acetylcholine, dopamine,norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A andC Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain, JNeurochem 51 (2); 522-527:1988) CGRP, substance P and glutamate(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks GlutamateExocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.Biochem 165; 675-681:1987. Thus, when adequate concentrations are used,stimulus-evoked release of most neurotransmitters is blocked bybotulinum toxin. See e.g. Pearce, L. B., Pharmacologic Characterizationof Botulinum Toxin For Basic Science and Medicine, Toxicon 35(9);1373-1412 at 1393; Bigalke H., et al., Botulinum A Neurotoxin InhibitsNon-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons inCulture, Brain Research 360; 318-324:1985; Habermann E., Inhibition byTetanus and Botulinum A Toxin of the release of [ ³ H]Noradrenaline and[ ³ H]GABA From Rat Brain Homogenate, Experientia 44; 224-226:1988,Bigalke H., et al., Tetanus Toxin and Botulinum A Toxin Inhibit Releaseand Uptake of Various Transmitters, as Studied with ParticulatePreparations From Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's ArchPharmacol 316; 244-251:1981, and; Jankovic J. et al., Therapy WithBotulinum Toxin, Marcel Dekker, Inc., (1994), page 5.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures. Allthe botulinum toxin serotypes are initially synthesized as inactivesingle chain proteins which must be cleaved or nicked by proteases tobecome neuroactive. The bacterial strains that make botulinum toxinserotypes A and G possess endogenous proteases and serotypes A and G cantherefore be recovered from bacterial cultures in predominantly theiractive form. In contrast, botulinum toxin serotypes C₁, D and E aresynthesized by nonproteolytic strains and are therefore typicallyunactivated when recovered from culture. Serotypes B and F are producedby both proteolytic and nonproteolytic strains and therefore can berecovered in either the active or inactive form. However, even theproteolytic strains that produce, for example, the botulinum toxin typeB serotype only cleave a portion of the toxin produced. The exactproportion of nicked to unnicked molecules depends on the length ofincubation and the temperature of the culture. Therefore, a certainpercentage of any preparation of, for example, the botulinum toxin typeB toxin is likely to be inactive, possibly accounting for the knownsignificantly lower potency of botulinum toxin type B as compared tobotulinum toxin type A. The presence of inactive botulinum toxinmolecules in a clinical preparation will contribute to the overallprotein load of the preparation, which has been linked to increasedantigenicity, without contributing to its clinical efficacy.Additionally, it is known that botulinum toxin type B has, uponintramuscular injection, a shorter duration of activity and is also lesspotent than botulinum toxin type A at the same dose level.

High quality crystalline botulinum toxin type A can be produced from theHall A strain of Clostridium botulinum with characteristics of ≧3×10⁷U/mg, an A₂₆₀/A₂₇₈ Of less than 0.60 and a distinct pattern of bandingon gel electrophoresis. The known Shantz process can be used to obtaincrystalline botulinum toxin type A, as set forth in Shantz, E. J., etal, Properties and use of Botulinum toxin and Other MicrobialNeurotoxins in Medicine, Microbiol Rev. 56; 80-99:1992. Generally, thebotulinum toxin type A complex can be isolated and purified from ananaerobic fermentation by cultivating Clostridium botulinum type A in asuitable medium. The known process can also be used, upon separation outof the non-toxin proteins, to obtain pure botulinum toxins, such as forexample: purified botulinum toxin type A with an approximately 150 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater; purified botulinum toxin type B with an approximately 156 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater, and; purified botulinum toxin type F with an approximately 155kD molecular weight with a specific potency of 1-2×10⁷ LD₅₀ U/mg orgreater.

Botulinum toxins and/or botulinum toxin complexes can be obtained fromList Biological Laboratories, Inc., Campbell, Calif.; the Centre forApplied Microbiology and Research, Porton Down, U.K.; Wako (Osaka,Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals ofSt Louis, Mo. Pure botulinum toxin can also be used to prepare apharmaceutical composition.

As with enzymes generally, the biological activities of the botulinumtoxins (which are intracellular peptidases) is dependant, at least inpart, upon their three dimensional conformation. Thus, botulinum toxintype A is detoxified by heat, various chemicals surface stretching andsurface drying. Additionally, it is known that dilution of the toxincomplex obtained by the known culturing, fermentation and purificationto the much, much lower toxin concentrations used for pharmaceuticalcomposition formulation results in rapid detoxification of the toxinunless a suitable stabilizing agent is present. Dilution of the toxinfrom milligram quantities to a solution containing nanograms permilliliter presents significant difficulties because of the rapid lossof specific toxicity upon such great dilution. Since the toxin may beused months or years after the toxin containing pharmaceuticalcomposition is formulated, the toxin can stabilized with a stabilizingagent such as albumin and gelatin.

A commercially available botulinum toxin containing pharmaceuticalcomposition is sold under the trademark BOTOX® (available from Allergan,Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxintype A complex, albumin and sodium chloride packaged in sterile,vacuum-dried form. The botulinum toxin type A is made from a culture ofthe Hall strain of Clostridium botulinum grown in a medium containingN-Z amine and yeast extract. The botulinum toxin type A complex ispurified from the culture solution by a series of acid precipitations toa crystalline complex consisting of the active high molecular weighttoxin protein and an associated hemagglutinin protein. The crystallinecomplex is re-dissolved in a solution containing saline and albumin andsterile filtered (0.2 microns) prior to vacuum-drying. The vacuum-driedproduct is stored in a freezer at or below −5° C.

BOTOX® can be reconstituted with sterile, non-preserved saline prior tointramuscular injection. Each vial of BOTOX® contains about 100 units(U) of Clostridium botulinum toxin type A purified neurotoxin complex,0.5 milligrams of human serum albumin and 0.9 milligrams of sodiumchloride in a sterile, vacuum-dried form without a preservative.

To reconstitute vacuum-dried BOTOX®, sterile normal saline without apreservative; (0.9% Sodium Chloride Injection) is used by drawing up theproper amount of diluent in the appropriate size syringe. Since BOTOX®may be denatured by bubbling or similar violent agitation, the diluentis gently injected into the vial. For sterility reasons BOTOX® ispreferably administered within four hours after the vial is removed fromthe freezer and reconstituted. During these four hours, reconstitutedBOTOX® can be stored in a refrigerator at about 2° C. to about 8° C.Reconstituted, refrigerated BOTOX® has been reported to retain itspotency for at least about two weeks. Sloop, Neurology, 48:249-53:1997.

It has been reported that botulinum toxin type A has been used inclinical settings as follows:

(1) about 75-125 units of BOTOX® per intramuscular injection (multiplemuscles) to treat cervical dystonia;(2) 5-10 units of BOTOX® per intramuscular injection to treat glabellarlines (brow furrows) (5 units injected intramuscularly into the procerusmuscle and 10 units injected intramuscularly into each corrugatorsupercilii muscle);(3) about 30-80 units of BOTOX® to treat constipation by intrasphincterinjection of the puborectalis muscle;(4) about 1-5 units per muscle of intramuscularly injected BOTOX® totreat blepharospasm by injecting the lateral pre-tarsal orbicularisoculi muscle of the upper lid and the lateral pre-tarsal orbicularisoculi of the lower lid.(5) to treat strabismus, extraocular muscles have been injectedintramuscularly with between about 1-5 units of BOTOX®, the amountinjected varying based upon both the size of the muscle to be injectedand the extent of muscle paralysis desired (i.e. amount of dioptercorrection desired).(6) to treat upper limb spasticity following stroke by intramuscularinjections of BOTOX® into five different upper limb flexor muscles, asfollows:(a) flexor digitorum profundus: 7.5 U to 30 U(b) flexor digitorum sublimus: 7.5 U to 30 U(c) flexor carpi ulnaris: 10 U to 40 U(d) flexor carpi radialis: 15 U to 60 U(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscleshas been injected at the same treatment session, so that the patientreceives from 90 U to 360 U of upper limb flexor muscle BOTOX® byintramuscular injection at each treatment session.(7) to treat migraine, pericranial injected (injected symmetrically intoglabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX®has showed significant benefit as a prophylactic treatment of migrainecompared to vehicle as measured by decreased measures of migrainefrequency, maximal severity, associated vomiting and acute medicationuse over the three month period following the 25 U injection.

Additionally, intramuscular botulinum toxin has been used in thetreatment of tremor in patients with Parkinson's disease, although ithas been reported that results have not been impressive. Marjama-Jyons,J., et al., Tremor-Predominant Parkinson's Disease, Drugs & Aging 16(4);273-278:2000.

It is known that botulinum toxin type A can have an efficacy for up to12 months (European J. Neurology 6 (Supp 4): S111-S1150:1999), and insome circumstances for as long as 27 months, when used to treat glands,such as in the treatment of hyperhydrosis. See e.g. Bushara K.,Botulinum toxin and rhinorrhea, Otolaryngol Head Neck Surg 1996;114(3):507, and The Laryngoscope 109:1344-1346:1999. However, the usualduration of an intramuscular injection of Botox® is typically about 3 to4 months.

The success of botulinum toxin type A to treat a variety of clinicalconditions has led to interest in other botulinum toxin serotypes. Twocommercially available botulinum type A preparations for use in humansare BOTOX® available from Allergan, Inc., of Irvine, Calif., andDysport® available from Beaufour Ipsen, Porton Down, England. ABotulinum toxin type B preparation (MyoBloc®) is available from ElanPharmaceuticals of San Francisco, Calif.

In addition to having pharmacologic actions at the peripheral location,botulinum toxins may also have inhibitory effects in the central nervoussystem. Work by Weigand et al, Naunyn-Schmiedeberg's Arch. Pharmacol.1976; 292, 161-165, and Habermann, Naunyn-Schmiedeberg's Arch.Pharmacol. 1974; 281, 47-56 showed that botulinum toxin is able toascend to the spinal area by retrograde transport. As such, a botulinumtoxin injected at a peripheral location, for example intramuscularly,may be retrograde transported to the spinal cord.

U.S. Pat. No. 5,989,545 discloses that a modified clostridial neurotoxinor fragment thereof, preferably a botulinum toxin, chemically conjugatedor recombinantly fused to a particular targeting moiety can be used totreat pain by administration of the agent to the spinal cord.

It has been reported that use of a botulinum toxin to treat variousspasmodic muscle conditions can result in reduced depression andanxiety, as the muscle spasm is reduced. Murry T., et al., Spasmodicdysphonia; emotional status and botulinum toxin treatment, ArchOtolaryngol 1994 March; 120(3): 310-316; Jahanshahi M., et al.,Psychological functioning before and after treatment of torticollis withbotulinum toxin, J Neurol Neurosurg Psychiatry 1992; 55(3): 229-231.Additionally, German patent application DE 101 50 415 A1 discussesintramuscular injection of a botulinum toxin to treat depression andrelated affective disorders.

A botulinum toxin has also been proposed for or has been used to treatskin wounds (U.S. Pat. No. 6,447,787), various autonomic nervedysfunctions (U.S. Pat. No. 5,766,605), post-operative pain and visceralpain (U.S. Pat. No. 6,464,986), neuralgia pain (U.S. patent applicationSer. No. 630,587), hair growth and hair retention (U.S. Pat. No.6,299,893), dental related ailments (U.S. provisional patent applicationSer. No. 60/418,789), fibromyalgia (U.S. Pat. No. 6,623,742), variousskin disorders (U.S. patent application Ser. No. 10/731,973), motionsickness (U.S. patent application Ser. No. 752,869), psoriasis anddermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. No.6,423,319) various cancers (U.S. Pat. No. 6,139,845), smooth muscledisorders (U.S. Pat. No. 5,437,291), down turned mouth corners (U.S.Pat. No. 6,358,917), nerve entrapment syndromes (U.S. patent application2003 0224019), various impulse disorders (U.S. patent application Ser.No. 423,380), acne (WO 03/011333) and neurogenic inflammation (U.S. Pat.No. 6,063,768). Controlled release toxin implants are known (see e.g.U.S. Pat. Nos. 6,306,423 and 6,312,708) as is transdermal botulinumtoxin administration (U.S. patent application Ser. No. 10/194,805).

Botulinum toxin type A has been used to treat epilepsia partialiscontinua, a type of focal motor epilepsy. Bhattacharya K., et al., Noveluses of botulinum toxin type A: two case reports, Mov Disord 2000;15(Suppl 2):51-52.

Additionally, a botulinum toxin may have an effect to reduce inducedinflammatory pain in a rat formalin model. Aoki K., et al, Mechanisms ofthe antinociceptive effect of subcutaneous Botox: Inhibition ofperipheral and central nociceptive processing, Cephalalgia 2003September; 23(7):649. Furthermore, it has been reported that botulinumtoxin nerve blockage can cause a reduction of epidermal thickness. Li Y,et al., Sensory and motor denervation influences epidermal thickness inrat foot glabrous skin, Exp Neurol 1997; 147:452-462 (see page 459).Finally, it is known to administer a botulinum toxin to the foot totreat excessive foot sweating (Katsambas A., et al., Cutaneous diseasesof the foot: Unapproved treatments, Clin Dermatol 2002November-December; 20(6):689-699; Sevim, S., et al., Botulinum toxin-Atherapy for palmar and plantar hyperhidrosis, Acta Neurol Belg 2002December; 102(4):167-70), spastic toes (Suputtitada, A., Local botulinumtoxin type A injections in the treatment of spastic toes, Am J Phys MedRehabil 2002 October; 81(10):770-5), idiopathic toe walking (Tacks, L.,et al., Idiopathic toe walking: Treatment with botulinum toxin Ainjection, Dev Med Child Neurol 2002; 44(Suppl 91):6), and foot dystonia(Rogers J., et al., Injections of botulinum toxin A in foot dystonia,Neurology 1993 April; 43(4 Suppl 2)).

Furthermore, a botulinum toxin has been used to treat many types ofheadache, such as tension headache, (see eg U.S. Pat. No. 6,458,365),migraine headache pain (see eg U.S. Pat. No. 5,714,468), and sinusheadache (see U.S. Pat. No. 6,838,434). When a patient who has aheadache or who has a propensity to have a headache is administered abotulinum toxin (to treat the headache and/or to prevent occurrence of aheadache) the patient can respond to the administered botulinum toxin invarying ways, meaning that the botulinum toxin can be totally effective,partially effective or not effective at all to treat the headache and/orto prevent occurrence of a headache. Clearly it could benefit patientcare, conserve physician time and prevent unnecessary use of apharmaceutical if it could be determined prior to administration of abotulinum toxin if use of the botulinum for a particular patient will beeffective to treat a headache and/or to prevent development of aheadache.

What is needed therefore is a method for determining prior toadministration of a botulinum toxin to a patient who has a headache orwho has a propensity to have a headache, if the botulinum toxin will beeffective in that patient.

SUMMARY

The present invention meets this need and provides methods fordetermining prior to administration of a botulinum toxin to a patientwho has a headache or who has a propensity to have a headache if thebotulinum toxin will be effective in that patient.

The following definitions apply herein:

“About” means “that the item, parameter or term so qualified encompassesa range of plus or minus ten percent above and below the value of thestated item, parameter or term.

“Alleviating” means a reduction in the occurrence of a pain, of aheadache pain. Thus, alleviating includes some reduction, significantreduction, near total reduction, and total reduction. An alleviatingeffect may not appear clinically for between 1 to 7 days afteradministration of a botulinum toxin to a patient.

“Botulinum toxin” means a neurotoxin produced by Clostridium botulinum,as well as modified, recombinant, hybrid and chimeric botulinum toxins.A recombinant botulinum toxin can have the light chain and/or the heavychain thereof made recombinantly by a non-Clostridial species.“Botulinum toxin,” as used herein, encompasses the botulinum toxinserotypes A, B, C, D, E, F and G. “Botulinum toxin,” as used herein,also encompasses both a botulinum toxin complex (i.e. the 300, 600 and900 kDa complexes) as well as pure botulinum toxin (i.e. the about 150kDa neurotoxic molecule), all of which are useful in the practice of thepresent invention. “Purified botulinum toxin” means a pure botulinumtoxin or a botulinum toxin complex that is isolated, or substantiallyisolated, from other proteins and impurities which can accompany thebotulinum toxin as it is obtained from a culture or fermentationprocess. Thus, a purified botulinum toxin can have at least 90%,preferably more than 95%, and most preferably more than 99% of thenon-botulinum toxin proteins and impurities removed. The botulinum C₂and C₃ cytotoxins, are not botulinum neurotoxins, and are excluded fromthe scope of the present invention.

An “exploding headache” or “exploding headache pain” is a headache thatis perceived by the patient as being or as including a pain from theinside to the outside of the patient's head.

An “imploding headache” or “imploding headache pain” is a headache thatis perceived by the patient as being or as including a pain from theoutside to the inside of the patient's head.

“Local administration” means administration (i.e. by a subcutaneous,intramuscular, subdermal or transdermal route) of a pharmaceutical agentto or to the vicinity of a muscle or of a subdermal location or in thehead of a patient by a non-systemic route. Thus, local administrationexcludes systemic (i.e. to the blood circulation system) routes ofadministration, such as intravenous or oral administration. Peripheraladministration means administration to the periphery (i.e. to a locationon or within a limb, trunk or head of a patient) as opposed to avisceral or gut (i.e. to the viscera) administration.

“Treating” means to alleviate (or to eliminate) at least one symptom ofa headache pain either temporarily or permanently.

A patient “free of headache” after administration of a botulinum toxinmeans that the patient does not experience a headache for at least a twoweek period after administration of the botulinum toxin.

A patient “partially free of headache” after administration of abotulinum toxin means that the patient experiences a less than 50%reduction in headache present days after administration of the botulinumtoxin. For example, if prior to administration of a botulinum toxin thepatient experienced headache on six days in a two week period and afteradministration of the botulinum toxin the patient experiences headacheon four days in a two week period, that patient can be said to bepartially free of headache after administration of the botulinum toxin.

A patient “substantially free of headache” after administration of abotulinum toxin means that the patient experiences a greater than 50%reduction in headache present days after administration of the botulinumtoxin. For example, if prior to administration of a botulinum toxin thepatient experienced headache on six days in a two week period and afteradministration of the botulinum toxin the patient experiences headacheon two days in a two week period, that patient can be said to besubstantially free of headache after administration of the botulinumtoxin.

“Modified botulinum toxin” means a botulinum toxin that has had at leastone of its amino acids deleted, modified, or replaced, as compared to anative botulinum toxin. Additionally, the modified botulinum toxin canbe a recombinantly produced neurotoxin, or a derivative or fragment of arecombinantly made neurotoxin. A modified botulinum toxin retains atleast one biological activity of the native botulinum toxin, such as,the ability to bind to a botulinum toxin receptor, or the ability toinhibit neurotransmitter release from a neuron. One example of amodified botulinum toxin is a botulinum toxin that has a light chainfrom one botulinum toxin serotype (such as serotype A), and a heavychain from a different botulinum toxin serotype (such as serotype B).Another example of a modified botulinum toxin is a botulinum toxincoupled to a neurotransmitter, such as substance P.

Our invention includes a method for treating a headache by selecting apatient determined to be responsive to administration of a botulinumneurotoxin for treatment of a headache by determining that the patienthas or has a propensity to have an imploding and/or ocular headachepain, and administering a botulinum toxin to the selected patientthereby treating the headache. The botulinum neurotoxin used can be abotulinum toxin type A, B, C, D, E, F or G. Preferably, the botulinumtoxin is a botulinum toxin type A. The botulinum neurotoxin can beadministered in an amount of between about 1 unit and about 10,000units.

The botulinum toxin administration can be by a local administration,such as an intramuscular or subcutaneous administration to a location onor within a head of a patient, to a facial muscle of the patient and orto a forehead of the patient. The local administration of the botulinumtoxin can be to a subdermal location or to a muscle location from whichthe patient perceives a pain to arise. The headache treated by ourinvention can be a migraine headache.

Our invention also encompasses a method for treating a migraine headacheby selecting a patient determined to be responsive to administration ofa botulinum neurotoxin for treatment of a migraine headache bydetermining that the patient has or has a propensity to have animploding and/or ocular headache pain, followed by local administrationof between about 1 unit and about 1,500 units of a botulinum toxin typeA to the patient, thereby treating the migraine headache,

Administration of the botulinum toxin can be by a transdermal route(i.e. by application of a botulinum toxin in a cream, patch or lotionvehicle), subdermal route (i.e. subcutaneous or intramuscular), orintradermal route of administration. Additionally, the botulinum toxincan be administered as a monotherapy or in conjunction with othermedications, such as a triptan.

The dose of a botulinum toxin used according to the present invention ispreferably less than the amount of a botulinum toxin that would be usedto paralyze a muscle, since an intent of administration of a botulinumtoxin according to the present invention is not to paralyze a muscle butto reduce a pain sensory output from sensory neurons located in or on amuscle, or in or under the skin.

Our invention also includes a method for improving a responsiveness of apatient to a treatment of a headache with a botulinum neurotoxin byidentifying a patient who has or has a propensity to have an implodingand/or ocular headache pain, and administering a botulinum neurotoxin tothe patient, thereby treating the headache, wherein the identificationof the patient with an imploding and/or ocular headache is predictive ofincreased responsiveness to the treatment of headache with the botulinumneurotoxin toxin.

Another embodiment of our invention is a method for identifying apatient with increased responsiveness to treatment of a headache with abotulinum neurotoxin by screening a population of patients to identifythose patients who have or who have a propensity to have an implodingand/or ocular headache pain, wherein the identification of a patient whohas or has a propensity to have an imploding headache is predictive ofincreased responsiveness to the treatment of a headache pain with abotulinum neurotoxin.

Finally, our invention includes a method for selecting from a populationof patients with headache or with a propensity to have a headache, thosepatients whose headache will respond to administration of a botulinumneurotoxin by identifying from a population of patients with headache orwith a propensity to have a headache those patients who have or who havea propensity to have an imploding and/or ocular headache pain.

Botulinum toxin type A is a preferred botulinum toxin. The botulinumtoxin can be administered in an amount of between about 1 unit and about3,000 units. The local administration of the botulinum toxin can be toor to a vicinity of where the patient experiences or is predisposed toexperience pain. Alternately, the local administration can be byintramuscular injection or to a subdermal location from which thepatient perceives the existence of a pain to arise, typically at theforehead.

DRAWINGS

The following drawings are presented to assist understanding of aspectsand features of the present invention.

FIG. 1 is bar graph which shows the effects of a botulinum toxin type A(i.e. Botox) administration on frequency, duration and pain intensity ofmigraine in responders vs. non-responders.

FIG. 2 is a diagram which illustrates a possible effect on extracranialnerves as a mechanism of action to explain how a botulinum toxin (suchas BOTOX) can treat migraine.

FIG. 3 is two anatomical diagrams showing locations for intramuscularinjections of a botulinum toxin for a treatment of migraine.

FIG. 4 is a bar graph which shows the effects of botulinum toxin type A(Botox) administration on the number of migraine days per month inmigraine patients with imploding, ocular or exploding headache painheadache.

DESCRIPTION

The present invention is based on the discovery that a headache such asa migraine headache can be by treated by selecting for patients withimploding headache (i.e. an outside to inside pain perception) and/orocular headache (as opposed to selecting patients with explodingheadache (i.e. an inside to outside pain perception). Concomitantly, thepresent invention is based on the discovery that a headache such as amigraine headache can be by treated by selecting for treatment thosepatients who do not predominantly have or who do not have at all anexploding headache (i.e. an inside to outside pain perception).

We have found that patients who have imploding and/or ocular headachepain respond well to treatment with a botulinum toxin, whereas patientswho have exploding headache do not respond well to treatment with abotulinum toxin.

A patient with a headache (such as a migraine headache) for whomadministration of a botulinum toxin results in alleviation of a symptom(such as a pain symptom) of the headache can be referred to as aresponder. Similarly, a patient with a propensity or a predisposition toexperience headaches (such as migraine headaches) for whomadministration of a botulinum toxin results in a prophylactic reductionin the number, duration and/or intensity of the headaches experiencescan also referred to as a responder.

A patient with a headache (such as a migraine headache) for whomadministration of a botulinum toxin does not result in a significant orsubstantial alleviation of a symptom (such as a pain symptom) of theheadache can be referred to as a non-responder. Similarly, a patientwith a propensity or a predisposition to experience headaches (such asmigraine headaches) for whom administration of a botulinum toxin doesnot result in a significant or substantial prophylactic reduction in thenumber, duration and/or intensity of the headaches experiences can alsoreferred to as a non-responder.

Thus, as shown by FIG. 1, patients can respond very differently toadministration of a botulinum toxin (such as Botox) to treat a migraineheadache, depending upon whether the patient is a responder or anon-responder. Clearly, a patient that is a non-responder should not beadministered a botulinum toxin to treat a headache because to do soprovides medication to which the patient will not respond to or to whichhe will respond poorly. Such unnecessary medication can be potentiallyinjurious to the patient's health, as well as amounting to a waste ofmedication and physician time.

It is important to note that the method of administration of a botulinumtoxin (including the characteristics of fixed site dose, follow the paindosing, multiple sites, single site, high dose or low dose) are notimportant or significant characteristics of our invention. Thesignificant characteristic of our invention is to select (foradministration of a botulinum toxin to treat a headache and/or toprevent development of a headache) for a patient who has an implodingheadache and not select a patient who has an exploding headache. We havefound that a patient who has an imploding headache pain show a greaterreduction in headache pain and/or in the number of headache free days(upon administration of a botulinum toxin using a fixed site dose,follow the pain dosing, multiple sites, single site, high dose or lowdose of the botulinum toxin) than will a patient who has an explodingheadache pain.

A headache can be treated by local administration of a therapeuticallyeffective amount of a botulinum toxin. Thus, a botulinum toxin (such asa botulinum toxin serotype A, B, C₁, D, E, F or G) can be injected (i.e.intramuscular injection) into or in the vicinity where a patient isexperiencing the pain to thereby suppress the pain or prevent itsoccurrence. Alternately, the botulinum toxin can be administered to anintradermal or subdermal pain sensory neuron thereby suppressing andtreating a headache.

We have developed a method for treating a patient with a headache with abotulinum toxin with a high probability that the patient will respond tothe botulinum toxin, that is that a symptom of his headache will bealleviated. This treatment method is base upon a method for selectingfor treatment patients who are responders. According to our invention,patients who are determined to be non-responders are not administered abotulinum toxin to treat their headache.

Responders are selected for by determining if the patient has animploding headache or an exploding headache. We found that in a group of34 patients with imploding headache 32 (91%) responded to administrationof a botulinum toxin. On the other hand in a separate group of 27patient with exploding headache we found that 24 (92%) did not respondto administration of the botulinum toxin. Thus, we determined thatpatients with imploding headache are responders, whereas patients withexploding headache are non-responders.

Various injection techniques can be used to treat a headache with abotulinum toxin. For example single or multiple injections have beenused. Additionally, the botulinum toxin injection can be at a fixed siteor sites or a “follow the pain” (injections tailored to the sites wherethe patient perceives the pain to arise from). See eg. Kriegler J., etal., Single site Botox™ injection: Effective treatment for migraineheadaches, Headache 2006 May; 46(5):849; LaButta R., et al.,Effectiveness of botulinum toxin type-A in the treatment of migraineheadache: A randomized controlled trial, Neurology 2005 March; 64(Suppl1), and; Crnac, M., et al., Individual injection scheme in the treatmentof headache with botulinum toxin, J Neurol 2004; 251 (Suppl 1):I/43 A9.

For example, a botulinum toxin can be administered intramuscularly in anaverage of up to 20 separate injections to each patient. The botulinumtoxin can be administered at up to seven different muscles (i.e. 20total injections into 7 muscles). From example, about 100 to 300 unitsof a botulinum toxin such as BOTOX can be administered to a patient.

The botulinum toxin (i.e. Botox) can be administered (23-58 injectionsof 105-260 units in 6-7 muscle areas) determined based on the paindistribution pattern and the severity of pain in the particular musclearea of the patient. The patient can be injected in one or more of 6muscle areas; frontal/glabellar, occipitalis, temporalis, semispinalis,splenius capitis, and trapezius muscles, as shown in Table 1 and theFIG. 3.

TABLE 1 Preferred Dose and Injection Sites Total Dose Muscle Area Numberof Units Bilateral Injection (Botox U) Frontal/Glabellar 25–40 No 25–40Occipitalis 10 Yes 20 Temporalis 10–25 Yes 20–50 Masseter (optional) 0–25 Yes  0–50 Trapezius 10–30 Yes 20–60 Semispinalis  5–10 Yes 10–20Splenius capitis  5–10 Yes 10–20 Total Dose Range 105–260

Administration of a botulinum toxin to a head, neck or shoulder locationmay act to block extracranial nerves which act to rely sensory (pain)signals from the meninges, bone and scalp to a central (CNS) location,as illustrate by FIG. 2. Thus, it is known that muscles have a complexsystem of innervation and sensory output. Thus, anterior motor neuronslocated in each segment of the anterior horns of the spinal cord graymatter give rise to efferent alpha motor neurons and efferent gammamotor neurons that leave the spinal cord by way of the anterior roots toinnervate skeletal (extrafusal) muscle fibers. The alpha motor neuronscause contraction of extrafusal skeletal muscle fibers while the gammamotor neurons innervate the intrafusal fibers of skeletal muscle. Aswell as excitation by these two types of efferent anterior motor neuronprojections, there are additional, afferent sensory neurons whichproject from muscle spindle and golgi tendon organs and act to transmitinformation regarding various muscle parameter status to the spinalcord, cerebellum and cerebral cortex. These efferent motor neurons whichrelay sensory information from the muscle spindle include type Ia andtype II sensory afferent neurons. See e.g. pages 686-688 of Guyton A. C.et al., Textbook of Medical Physiology, W.B. Saunders Company 1996,ninth edition.

Significantly, it has been determined that a botulinum toxin can act toreduce transmission of sensory information from muscle type la afferentneurons. Aoki, K., Physiology and pharmacology of therapeutic botulinumneurotoxins, in Kreyden, O., editor, Hyperhydrosis and botulinum toxinin dermatology, Basel, Karger; 2002; 30: pages 107-116, at 109-110. Andit has been hypothesized that botulinum toxin can have a direct effectupon muscle cell sensory afferents and modify signals from theseafferents to the central nervous system. See e.g. Brin, M., et al.,Botulinum toxin type A: pharmacology, in Mayer N., editor, Spasticity:etiology, evaluation, management and the role of botulinum toxin, 2002;pages 110-124, at 112-113; Cui, M., et al., Mechanisms of theantinociceptive effect of subcutaneous BOTOX®: inhibition of peripheraland central nociceptive processing, Naunyn Schmiedebergs Arch Pharmacol2002; 365 (supp 2): R17; Aoki, K., et al., Botulinum toxin type A andother botulinum toxin serotypes: a comparative review of biochemical andpharmacological actions, Eur J. Neurol 2001: (suppl 5); 21-29. Thus, ithas been demonstrated that botulinum toxin can cause an altered sensoryoutput from muscle to CNS and brain.

Importantly, the sensory neurons from which afferent output is to beinhibited by a method according to the present invention need not belocated on or within a muscle, but can be in an intradermal or subdermallocation.

Thus, pain can be due to sensory input from afferent facial areaneurons. Administration of a botulinum toxin to a facial muscles or skinto reduce sensory output from the muscle can result in alleviation ofand prevention of pain.

Our invention also includes a method for treating an ocular headache,such as an ocular migraine headache by administration of a botulinumtoxin by infusing the botulinum toxin behind the globe of the eye totarget C and A-delta pain fibers present in this peri-bulbar location inthe skull, thereby following the neural innervation.

The amount of the botulinum toxin administered according to a methodwithin the scope of the disclosed invention can vary according to theparticular characteristics of the pain being treated, including itsseverity and other various patient variables including size, weight,age, and responsiveness to therapy. To guide the practitioner,typically, no less than about 1 unit and no more than about 70 units ofa botulinum toxin type A (such as BOTOX® is administered per injectionsite (i.e. to each muscle portion injected), per patent treatmentsession. For a botulinum toxin type A such as DYSPORT®, no less thanabout 4 units and no more about 280 units of the botulinum toxin type Aare administered per injection site, per patent treatment session. For abotulinum toxin type B such as MYOBLOC®, no less than about 40 units andno more about 2800 units of the botulinum toxin type B are administeredper injection site, per patent treatment session. Less than about 1, 4or 40 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively) can fail toachieve a desired therapeutic effect, while more than about 70, 280 or2800 units (of BOTOX®, DYSPORT® and MYOBLOC® respectively) can result insignificant muscle hypotonicity, weakness and/or paralysis.

More preferably: for BOTOX® no less than about 5 units and no more about60 units of a botulinum toxin type A; for DYSPORT® no less than about 20units and no more than about 240 units, and; for MYOBLOC®, no less thanabout 200 units and no more than about 2400 units are, respectively,administered per injection site, per patent treatment session.

Most preferably: for BOTOX® no less than about 10 units and no moreabout 50 units of a botulinum toxin type A; for DYSPORT® no less thanabout 40 units and no more than about 200 units, and; for MYOBLOC®, noless than about 400 units and no more than about 2000 units are,respectively, administered per injection site, per patent treatmentsession. It is important to note that there can be multiple injectionsites (i.e. a pattern of injections) for each patient treatment session.

Generally, the total amount of BOTOX®, DYSPORT® or MYOBLOC®, suitablefor administration to a patient according to the methods of theinvention disclosed herein should not exceed about 300 units, about1,500 units or about 15,000 units respectively, per treatment session.For XEOMIN® (a 150 kDa botulinum toxin type A formulation available fromMerz Pharmaceuticals, Potsdam, Germany) about 1× to about 2× the amountsof BOTOX® set forth above can be used in each instance.

When BOTOX® is administered, each vial of BOTOX® contains 100 units ofClostridium botulinum toxin type A (purified), 0.5 mg albumin (human),and 0.9 mg sodium chloride in a sterile, vacuum-dried form without apreservative. One unit corresponds to the calculated median lethalintraperitoneal dose (LD₅₀) in mice. Preferably, the vials are stored ina freezer between −20° C. and −5° C. before use. Reconstitution is with0.9% sterile saline (without preservatives) for injection.

Examples of Clostridial toxins within the scope of the present inventioninclude neurotoxins made by Clostridium botulinum, Clostridium butyricumand Clostridium beratti species. In addition, the botulinum toxins usedin the methods of the invention may be a botulinum toxin selected from agroup of botulinum toxin types A, B, C, D, E, F, and G. In oneembodiment of the invention, the botulinum neurotoxin administered tothe patient is botulinum toxin type A. Botulinum toxin type A isdesirable due to its high potency in humans, ready availability, andknown use for the treatment of skeletal and smooth muscle disorders whenlocally administered by intramuscular injection. The present inventionalso includes the use of (a) Clostridial neurotoxins obtained orprocessed by bacterial culturing, toxin extraction, concentration,preservation, freeze drying, and/or reconstitution; and/or (b) modifiedor recombinant neurotoxins, that is neurotoxins that have had one ormore amino acids or amino acid sequences deliberately deleted, modifiedor replaced by known chemical/biochemical amino acid modificationprocedures or by use of known host cell/recombinant vector recombinanttechnologies, as well as derivatives or fragments of neurotoxins somade. These neurotoxin variants retain the ability to inhibitneurotransmission between or among neurons, and some of these variantsmay provide increased durations of inhibitory effects as compared tonative neurotoxins, or may provide enhanced binding specificity to theneurons exposed to the neurotoxins. These neurotoxin variants may beselected by screening the variants using conventional assays to identifyneurotoxins that have the desired physiological effects of inhibitingneurotransmission.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient.

Although the composition may only contain a single type of neurotoxin,such as botulinum toxin type A, as the active ingredient to suppressneurotransmission, other therapeutic compositions may include two ormore types of neurotoxins, which may provide enhanced therapeutictreatment of a headache. For example, a composition administered to apatient may include botulinum toxin type A and botulinum toxin type B.Administering a single composition containing two different neurotoxin'smay permit the effective concentration of each of the neurotoxins to belower than if a single neurotoxin is administered to the patient whilestill achieving the desired therapeutic effects. The compositionadministered to the patient may also contain other pharmaceuticallyactive ingredients, such as, protein receptor or ion channel modulators,in combination with the neurotoxin or neurotoxins. These modulators maycontribute to the reduction in neurotransmission between the variousneurons. For example, a composition may contain gamma aminobutyric acid(GABA) type A receptor modulators that enhance the inhibitory effectsmediated by the GABA_(A) receptor.

The botulinum neurotoxin may be administered by any suitable method asdetermined by the attending physician. The methods of administrationpermit the neurotoxin to be administered locally to a selected targettissue. Methods of administration include injection of a solution orcomposition containing the neurotoxin, as described above, and includeimplantation of a controlled release system that controllably releasesthe neurotoxin to the target tissue. Such controlled release systemsreduce the need for repeat injections. Diffusion of biological activityof a botulinum toxin within a tissue appears to be a function of doseand can be graduated. Jankovic J., et al Therapy With Botulinum Toxin,Marcel Dekker, Inc., (1994), page 150. Thus, diffusion of botulinumtoxin can be controlled to reduce potentially undesirable side effectsthat may affect the patient's cognitive abilities. For example, theneurotoxin can be administered so that the neurotoxin primarily effectsneural systems believed to be involved in the generation of pain and/orinflammation, and does not have negatively adverse effects on otherneural systems.

Local administration of a botulinum toxin, can provide a high, localtherapeutic level of the toxin. A controlled release polymer capable oflong term, local delivery of a Clostridial toxin to a target musclepermits effective dosing of a target tissue. A suitable implant, as setforth in U.S. Pat. No. 6,306,423 entitled “Neurotoxin Implant”, allowsthe direct introduction of a chemotherapeutic agent to a target tissuevia a controlled release polymer. The implant polymers used arepreferably hydrophobic so as to protect the polymer incorporatedneurotoxin from water induced decomposition until the toxin is releasedinto the target tissue environment.

Local administration of a botulinum toxin, according to the presentinvention, by injection or implant to a target tissue provides asuperior alternative to systemic administration of pharmaceuticals topatients to alleviate a headache.

The amount of a botulinum toxin selected for local administration to atarget tissue according to the present disclosed invention can be variedbased upon criteria such as the severity of the pain or type of headachebeing treated, the extent of muscle tissue to be treated, solubilitycharacteristics of the neurotoxin toxin chosen as well as the age, sex,weight and health of the patient. For example, the extent of the area ofmuscle tissue influenced is believed to be proportional to the volume ofneurotoxin injected, while the quantity of the suppressant effect is,for most dose ranges, believed to be proportional to the concentrationof a botulinum toxin administered. Methods for determining theappropriate route of administration and dosage are generally determinedon a case by case basis by the attending physician. Such determinationsare routine to one of ordinary skill in the art (see for example,Harrison's Principles of Internal Medicine (1998), edited by AnthonyFauci et al., 14^(th) edition, published by McGraw Hill).

EXAMPLES

The following non-limiting example provides those of ordinary skill inthe art with specific preferred selection and treatment methods withinthe scope of the present invention and are not intended to limit thescope of the invention. In the following examples various modes ofnon-systemic administration of a Clostridial neurotoxin can be carriedout. For example, by intramuscular injection, subcutaneous injection orby implantation of a controlled release implant.

Example 1 Use of a Botulinum Toxin to Treat the Migraine of a Patientwith Imploding Headache Pain

A female patient, 48 years old complained of migraine headaches sincethe age of 12 and reported migraine family history. Before botulinumtoxin administration she suffered 20 migraine attacks a month, eachlasting a day with pain intensity of 7 on a scale of 0 to 10. Shedescribed the pain as feeling “like a very tight band across myforehead”, which was viewed as an outside to the inside the head pain,and she was therefore classified as having an imploding headache pain.The patient can be administered various doses of a botulinum toxin atvarious injection sites. For example, Botox can be administered at adose of about 5 Units at multiple (32) sites into the frontalis,glabellar, temporalis, occipitalis, splenius capitus, semispinalis,trapezius muscle groups for to a total dose of about 160 Units AfterBotox administration the patient experienced only one migraine attack amonth with a pain intensity of 3 on a scale of 0 to 10.

A botulinum toxin type B, C, D, E, F or G can be substituted for thebotulinum toxin type A used above.

Example 2 Selecting Migraine Patients with Imploding Headache PainVersus Exploding Headache Pain for Treatment with Botulinum Toxin

Seven patients with migraine headache who responded to administration ofa botulinum toxin to treat their migraine and seven additional patientswith migraine did not respond or who responded poorly to administrationof a botulinum toxin to treat their migraine were included in thisstudy. Significantly, it was determined through patent interviews thatthe non-responders were all patients who reported that their migraineincluded exploding headache pain (that is reported a perception by thepatient of having an inside to outside headache pain) with little or noimploding headache pain, and that the responders were all patients whoreported that their migraine included imploding headache pain (that isreported a perception by the patient of having an outside to insideheadache pain) with little or no exploding headache pain.

Each patient was administered a botulinum toxin type A (BOTOX®). Thepatients can be administered various doses of a botulinum toxin atvarious injection sites. For example, about 5 units of Botox can beinjected into injection sites in the frontalis, glabellar, temporalis,occipitalis, splenius capitus, semispinalis, and trapezius musclegroups. The total dose per patient can be between about 180 and about220 Units. The results are shown in Table 1, where “Change in HAFrequency Month” means the change in how many days a month the patienthas a headache after botulinum toxin administration; an arrow meansthere was a change to the number of days a month with headache to thenumber shown to the right of the arrow. “HA Duration (Days)” means howlong each headache lasts. “Change in Pain Intensity” means the intensityof the headache pain as perceived by the patients on a scale of 0 to 10.“NC” means no change.

As shown by Table 2, most non-responders did not have a change inmonthly headache frequency, duration of headache or pain intensity afterbotulinum toxin administration. As also shown by Table 1, mostresponders did have a change in monthly headache frequency, duration ofheadache or pain intensity after botulinum toxin administration.

TABLE 2 Comparison of effect of Effect of BOTOX ® on Non-RespondersVersus Responders Non-Responders Change in HA HA Change in Frequency/Duration Pain Patient Month (Days) Intensity 1 NC NC NC 2 3 → 2 5 → 3 NC3 NC NC NC 4 NC NC NC 5 NC NC NC 6 NC NC NC 7 NC NC 7 → 3 Responders HAHA Frequency/ Duration Change in HA Patient Month (Days) Intensity 8 8 →0 NC NC 9 30 → 0  NC NC 10  12 → 4* NC 10 → 5  11  8 → 2 3 → 1 NC 12  30→ 4  6 → 2 NC 13  30 → 30 NC 10 → 9  14  4 → 1 3 → 1 7 → 5

Example 3 Further Study Regarding Selecting Migraine Patients withImploding Headache Pain Versus Exploding Headache Pain for Treatmentwith Botulinum Toxin

We carried out a study to identify neurological symptoms that would tagepisodic-migraine patients who respond prophylactically to a botulinumtoxin type A treatment. Quite a few migraine patients have noticed aconsiderable decrease in attack frequency following botulinum toxininjections. Some migraineurs (patients with migraine) however do notexperience such improvement after a botulinum toxin type Aadministration. This study determined a marker that can tease outprospective responders from non-responders.

Patients were interviewed in the clinic for detailed migraine symptomsand medical history. Patients experiencing a >75% reduction in attackfrequency within 3 months of botulinum toxin type A treatment wereselected as responders. Patients who showed no change in attackfrequency were selected as non-responders. The interviewer had noknowledge of the patient's response to the botulinum toxin type Atreatment before the interview was completed.

Responders (n=35) experienced significant drops in the number ofattacks/month (12.7±1.7 before botulinum toxin type A vs. 1.5±0.4 aftertreatment), attack duration (1.7±0.2 vs. 0.5±0.1 days), and headacheintensity (9.1±0.2 vs. 4.4±0.6 pain score). Non-responders (n=24)yielded identical values before and after treatment: 10.5±1.6 vs.10.7±1.6 attacks/month; 1.4±0.2 vs. 1.4±0.2 days/attack; 8.0±1.4 vs.7.8±0.4 pain score. No difference was found between responders andnon-responders across the full array of the classic migraine symptoms.However, there was one clear difference between the two groups: 92% ofnon-responders described their headache as exploding (extreme pressureinside the head) whereas 89% of the responders described their headacheas imploding (extreme pressure outside the head) or ocular (extremepressure behind the eyeball). We conclude therefore that migraine withimploding or ocular headache was highly associated with successfulprevention of attacks using a botulinum toxin type A and that migrainewith exploding headache was highly associated with failure to blockmigraine attacks when a botulinum toxin type A was administered.

Example 4 Selecting Migraine Patients with Ocular Headache Pain versusExploding Headache Pain for Treatment with Botulinum Toxin

Patients have reported symptoms and effects of ocular migraine headachepain as follows: “I want to take a spoon and pull out my eye”; “my eyesare popping out”; “someone is jabbing a knife into my eye and I want totake my eye out”, and; “someone is pushing a finger into my eye”. Acommon aspect of ocular headache pain (synonymously ocular migraineheadache pain) is a feeling of pain in the eye, or in the eye socket oradjacent tissue. In one prospective, double blind study of patients withmigraine which included two patients with ocular headache pain, boththese migraine patients with ocular headache pain responded (becameheadache free) after administration of a botulinum toxin (BOTOX).Additionally, in a second retrospective, triple blind study (blinded asto investigator, patient and attending physician) of patients withmigraine which included eight patients with ocular headache pain, alleight of these migraine patients with ocular headache pain responded(became headache free) after administration of a botulinum toxin(BOTOX).

The results from Examples 1-4 can be summarized in FIG. 4 which showsthat selecting for migraine patients who have imploding headache painand/or ocular headache pain, as opposed to exploding headache pain,dramatically reduced the number of days per month, after administrationof a botulinum toxin type A (i.e. BOTOX), during which the patients hada migraine headache.

Example 5 Treatment of Migraine with Botulinum Toxin

A female patient, 32 years old complains of migraine headaches. Beforebotulinum toxin type B administration she suffers about 25 migraineattacks a month, each lasting most of a day with pain intensity of 8 ona scale of 0 to 10.

Based on her pain perception she is classified as having an implodingheadache pain. After administration of a botulinum toxin type B (1200units into the frontals and glabellar muscles, 800 units into theoccipitalis muscles and 200 units into the trapezius muscle) sheexperiences only one migraine attack a month with pain intensity of 1out of 10.

All references, articles, patents, applications and publications setforth above are incorporated herein by reference in their entireties.Although the present invention has been described in detail with regardto certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, each of the botulinum neurotoxins A, B, C, D, E, F and Gcan be effectively used in the methods of the present invention.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

1. A method for treating a headache, the method comprising the steps of:(a) selecting a patient determined to be responsive to administration ofa botulinum neurotoxin for treatment of a headache by determining thatthe patient has or has a propensity to have an imploding headache pain,and; (b) administering a botulinum toxin to the selected patient,thereby treating the headache.
 2. The method of claim 1, wherein thebotulinum neurotoxin is selected from the group consisting of botulinumtoxin types A, B, C, D, E, F and G.
 3. The method of claim 1, whereinthe botulinum neurotoxin is a botulinum toxin type A.
 4. The method ofclaim 1, wherein the botulinum neurotoxin is administered in an amountof between about 1 unit and about 10,000 units.
 5. The method of claim1, wherein the administration is by local administration.
 6. The methodof claim 1, wherein the local administration is intramuscular orsubcutaneous administration to a location on or within a head of apatient.
 7. The method of claim 6, wherein the local administration ofthe botulinum toxin is to a facial muscle of the patient.
 8. The methodof claim 6, wherein the local administration is to a forehead of thepatient
 9. The method of claim 6, wherein the local administration ofthe botulinum toxin is to a subdermal location or to a muscle locationfrom which the patient perceives a pain to arise.
 10. The method ofclaim 1, wherein the headache is a migraine headache.
 11. A method fortreating a migraine headache, the method comprising the steps of: (a)selecting a patient determined to be responsive to administration of abotulinum neurotoxin for treatment of a migraine headache by determiningthat the patient has or has a propensity to have an imploding headachepain, and; (b) local administration of between about 1 unit and about1,500 units of a botulinum toxin type A to the patient, thereby treatingthe migraine headache.
 12. The method of claim 11, wherein the botulinumneurotoxin is selected from the group consisting of botulinum toxintypes A, B, C, D, E, F and G.
 13. The method of claim 11, wherein thebotulinum neurotoxin is a botulinum toxin type A.
 14. The method ofclaim 11, wherein the botulinum neurotoxin is administered in an amountof between about 1 unit and about 10,000 units.
 15. The method of claim11, wherein the local administration is by intramuscular or subcutaneousadministration to a location on or within a head of a patient.
 16. Themethod of claim 11, wherein the local administration of the botulinumneurotoxin is to a facial muscle of the patient.
 17. The method of claim11, wherein the local administration is to a forehead of the patient 18.The method of claim 11, wherein the local administration of thebotulinum neurotoxin is to a subdermal location or to a muscle locationfrom which the patient perceives a pain to arise.
 19. A method forimproving a responsiveness of a patient to a treatment of a headachewith a botulinum neurotoxin, the method comprising the steps of: (a)identifying a patient who has or has a propensity to have an implodingheadache pain, and; (b) administering a botulinum neurotoxin to thepatient, thereby treating the headache, wherein the identification ofthe patient with an imploding headache, or with a propensity to have animploding headache pain, is predictive of increased responsiveness tothe treatment of headache with the botulinum neurotoxin toxin.
 20. Themethod of claim 19, wherein the botulinum neurotoxin is selected fromthe group consisting of botulinum toxin types A, B, C, D, E, F and G.21. The method of claim 19, wherein the botulinum neurotoxin is abotulinum toxin type A.
 22. The method of claim 19, wherein thebotulinum neurotoxin is administered in an amount of between about 1unit and about 10,000 units.
 23. The method of claim 18, wherein theheadache is a migraine headache.
 24. A method for identifying a patientwith increased responsiveness to treatment of a headache with abotulinum neurotoxin, the method comprising the step of screening apopulation of patients to identify those patients who have or who have apropensity to have an imploding headache pain, wherein theidentification of a patient who has or has a propensity to have animploding headache pain is predictive of increased responsiveness to thetreatment of a headache with a botulinum neurotoxin.
 25. A method forselecting from a population of patients with headache or with apropensity to have a headache, those patients whose headache willrespond to administration of a botulinum neurotoxin, the methodcomprising the step of identifying from a population of patients withheadache or with a propensity to have a headache those patients who haveor who have a propensity to have an imploding headache pain.
 26. Themethod of claim 25, wherein the botulinum neurotoxin is selected fromthe group consisting of botulinum toxin types A, B, C, D, E, F and G.27. The method of claim 25, wherein the botulinum neurotoxin is abotulinum toxin type A.
 28. The method of claim 25, wherein the headacheis a migraine headache.
 29. A method for treating a headache, the methodcomprising the steps of: (a) selecting a patient determined to beresponsive to administration of a botulinum neurotoxin for treatment ofa headache by determining that the patient has or has a propensity tohave an ocular headache pain, and; (b) administering a botulinum toxinto the selected patient, thereby treating the headache.
 30. The methodof claim 29, wherein the botulinum neurotoxin is selected from the groupconsisting of botulinum toxin types A, B, C, D, E, F and G.
 31. Themethod of claim 29, wherein the botulinum neurotoxin is a botulinumtoxin type A.
 32. The method of claim 29, wherein the botulinumneurotoxin is administered in an amount of between about 1 unit andabout 10,000 units.
 33. The method of claim 29, wherein theadministration is by local administration.
 34. The method of claim 33,wherein the local administration is intramuscular or subcutaneousadministration to a location on or within a head of a patient.
 35. Themethod of claim 29, wherein the local administration of the botulinumtoxin is to a facial muscle of the patient.
 36. The method of claim 33,wherein the local administration is to a forehead of the patient
 37. Themethod of claim 33, wherein the local administration of the botulinumtoxin is to a subdermal location or to a muscle location from which thepatient perceives a pain to arise.
 38. The method of claim 29, whereinthe headache is a migraine headache.
 39. A method for treating amigraine headache, the method comprising the steps of: (a) selecting apatient determined to be responsive to administration of a botulinumneurotoxin for treatment of a migraine headache by determining that thepatient has or has a propensity to have an ocular headache pain, and;(b) local administration of between about 1 unit and about 1,500 unitsof a botulinum toxin type A to the patient, thereby treating themigraine headache.
 40. The method of claim 39, wherein the botulinumneurotoxin is selected from the group consisting of botulinum toxintypes A, B, C, D, E, F and G.
 41. The method of claim 39, wherein thebotulinum neurotoxin is a botulinum toxin type A.
 42. The method ofclaim 39, wherein the botulinum neurotoxin is administered in an amountof between about 1 unit and about 10,000 units.
 43. The method of claim39, wherein the local administration is by intramuscular or subcutaneousadministration to a location on or within a head of a patient.
 44. Themethod of claim 39, wherein the local administration of the botulinumneurotoxin is to a facial muscle of the patient.
 45. The method of claim39, wherein the local administration is to a forehead of the patient 46.The method of claim 39, wherein the local administration of thebotulinum neurotoxin is to a subdermal location or to a muscle locationfrom which the patient perceives a pain to arise.
 47. A method forimproving a responsiveness of a patient to a treatment of a headachewith a botulinum neurotoxin, the method comprising the steps of: (a)identifying a patient who has or has a propensity to have an ocularheadache pain, and; (b) administering a botulinum neurotoxin to thepatient, thereby treating the headache, wherein the identification ofthe patient with an ocular headache pain, or with a propensity to havean ocular headache pain, is predictive of increased responsiveness tothe treatment of headache with the botulinum neurotoxin toxin.
 48. Themethod of claim 47, wherein the botulinum neurotoxin is selected fromthe group consisting of botulinum toxin types A, B, C, D, E, F and G.49. The method of claim 47, wherein the botulinum neurotoxin is abotulinum toxin type A.
 50. The method of claim 47, wherein thebotulinum neurotoxin is administered in an amount of between about 1unit and about 10,000 units.
 51. The method of claim 47, wherein theheadache is a migraine headache.
 52. A method for identifying a patientwith increased responsiveness to treatment of a headache with abotulinum neurotoxin, the method comprising the step of screening apopulation of patients to identify those patients who have or who have apropensity to have an ocular headache pain, wherein the identificationof a patient who has or has a propensity to have an ocular headache painis predictive of increased responsiveness to the treatment of a headachewith a botulinum neurotoxin.
 53. A method for selecting from apopulation of patients with headache or with a propensity to have aheadache, those patients whose headache will respond to administrationof a botulinum neurotoxin, the method comprising the step of identifyingfrom a population of patients with headache or with a propensity to havea headache those patients who have or who have a propensity to have anocular headache pain.
 54. The method of claim 53, wherein the botulinumneurotoxin is selected from the group consisting of botulinum toxintypes A, B, C, D, E, F and G.
 55. The method of claim 53, wherein thebotulinum neurotoxin is a botulinum toxin type A.
 56. The method ofclaim 53, wherein the headache is a migraine headache.